Three-dimensional live imaging in thick tissue is increasingly important in cell biology. One would like to understand cells in their natural context, follow behaviors traveling through a group of cells and watch mobile cells move through the cellular matrix. Unfortunately, high-resolution optical microscopes, capable of imaging subcellular features, are designed to image only the first micron below the coverslip. As the imaging plane is moved deeper into the sample, aberrations rapidly degrade the image. These aberrations are caused by the refractive index mismatch between the objective immersion medium and the sample mounting medium (Spherical aberrations) and refractive index variations within the sample itself (Sample-induced aberrations). Adaptive Optics (AO) is a technology that shows great promise for correcting these aberrations in optical imaging. AO corrects optical aberrations by measuring the wavefront with a wavefront sensor and then correcting the wavefront with a deformable mirror. AO has been used with great success in optical astronomy for correcting the wavefront aberrations caused by the earth's atmosphere. For this research project, adaptive optics technology will be incorporated into high-resolution wide-field microscopes to allow three-dimensional imaging of living biological samples at high-resolution many tens of microns below the coverslip. Separate microscopes will be built to correct spherical aberrations and sample- induced aberrations, and research will be done into wavefront sensors for biological samples. Then a final microscope will be designed that corrects both spherical and sample-induced aberrations. This research could have a tremendous impact on the resolution and sensitivity of fluorescence imaging into live tissue. Advances in medical science and public health depend upon scientific advances in our understanding of cell biology, including understanding the behavior of cells in living tissue. A microscope with adaptive-optics technology will enable high-resolution imaging deep into live tissue which will help answer important questions about cell behavior. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]